Later stages of Parkinson's disease are often characterized by motor fluctuations that include unpredictable and severely disabling periods of complete immobility ("off" periods). The most effective pharmacological treatments for "off' periods are dopamine agonists, with the dopamine agonist apomorphine especially effective. Apomorphine, however, suffers from low oral bioavailability and a low therapeutic index, which limit its clinical use. The aim of this proposal is to develop inhalation devices that deliver apomorphine and at least one other dopamine agonist drug rapidly into the blood stream, enabling patients to titrate their drug intake to the minimum effective dose, thus reducing side effects. Our company has developed a unique aerosol generation method that produces very small particles for efficient deep lung inhalation without any excipients or entrainers. This technique has already been proven to result in rapid systemic delivery of several FDA-approved drugs to mammals. In this Phase I grant, we will verify our ability to use this technology to deliver reliably and reproducibly a therapeutic amount of apomorphine as well as at least one other dopamine agonist compound. In a subsequent Phase II grant, we intend to build a delivery device with an optimized patient interface and complete animal pharmacokinetic and toxicology studies sufficient to initiate human clinical trials. Eventual clinical approval of a dopamine agonist inhalation device will allow patients with late stage Parkinson's disease to control their Disease more effectively, and thus increases their overall quality of life.